Current animal models of Parkinson's disease (PD) use high-dosages of dopamine (DA) neurotoxins to produce rapidly evolving lesions. We have recently shown that injection of the Gram (-) bacteriotoxin, lipopolysaccharide (LPS), into gravid female rats at embryonic (E) day 10.5 produces offspring born with fewer dopamine (DA) neurons. The 30-40% DA neuron loss routinely seen is still present after 4 months and presumed permanent. This DA neuron loss is similar to that seen in the PD patient since it is more pronounced in the lateral nigra and its ventral tier, spares the ventral tegmental area and calbindin immunoreactive DA neurons in the nigra, and is associated with reduced striatal DA and increased DA activity as well as tumor necrosis factor (TNFalpha). Exposure of these animals to the DA neurotoxin 6-hydroxydopamine (6OHDA) after 4 months, produces a greater inflammatory response and further DA cell loss. We hypothesize that the elevated DA activity and TNF seen in adult animals as a result of prenatal LPS treatment will lead to increased production of reactive oxygen species (ROS) that will eventually overwhelm ROS detoxification systems leading to further, progressive DA neuron loss as a result of aging or low dose exposure to 6OHDA. Based on this hypothesis we will study rats exposed to prenatal LPS and determine if further DA cell loss occurs with aging (through 21 months; Aim 1). Aim 2 will examine the combined effects of prenatal LPS and postnatal 6OHDA at various ages and determine if the combined effects of these two treatments is additive or synergistic and if the magnitude of the DA neuron loss as a result of these two neurotoxins increases with age. Whether or not animals exposed to prenatal LPS and 6OHDA at a young age exhibit a greater rate of DA neuron loss as they age compared with animals treated later in life, will be evaluated in Specific Aim 3. The successful implementation of these Specific Aims will address the notion that prenatal exposure to bacterial endotoxin is a risk factor for PD. Moreover, they would further demonstrate that prenatal infections such as bacterial vaginosis can interact with postnatal neurotoxin exposure to produce a gradual, protracted DA neuron loss that could be useful as a new animal model of PD.